Process for the synthesis of hydrogenofluoromethylenesulphonyl radical derivatives

ABSTRACT

The invention concerns a method for synthesis of hydrogenofluoromethylenesulphonyl radical derivatives, comprising: a) a step which consists in condensing a thiolate (that is a monoalkyl sulphide salt) with a compound having a sp; 3hybridized carbon bearing a hydrogen, a fluorine, a heavy halogen selected among chlorine, bromine and iodine and an electron-attracting group selected among fluorine and those whereof the; is not less than 0.2, advantageously than 0.4; b) a step which consists in oxidizing the compound obtained in step a). The invention is applicable to the synthesis of various compounds having a suphinyl or sulphonyl group.

This application is an application under 35 U.S.C. Section 371 ofInternational Application Number PCT/FR2003/001940 filed on Jun. 26,2003.

The subject matter of the present invention is a novel synthesis ofderivatives comprising a hydrofluoromethylenesulfonyl or -sulfinylradical.

It is targeted more particularly at the synthesis ofdifluoromethanesulfinic or -sulfonic acid derivatives and in particularthe acid proper, its salts and its acid chlorides.

The sulfonic acids carried by electron-withdrawing groups and inparticular carried by electron-withdrawing groups where the carboncarrying the sulfonic functional group also carries at least onefluorine are increasingly advantageous compounds, first because theymake it possible to give specific particular properties to medicamentsor to agricultural derivatives and, secondly, because they can act asconstituent components of salts for batteries, in particular “lithium”batteries.

Sulfonyl and sulfinyl halides should be indicated in particular amongadvantageous products. Mention may be made, among the halides, of thebromide, which is relatively unstable, the chloride and the fluoride.

The processes for producing these compounds are generally lengthy anddifficult or give relatively low yields, or else require the use ofparticularly extensive solvents or operating conditions.

If reference is made more specifically to difluoromethanesulfonic acid,sometimes known as diflic acid, its synthesis is not described to anygreat extent in the literature and requires the use of relativelyexpensive solvents and requires the formation of a large amount ofsalts.

This is why one of the aims of the present invention is to provide aprocess for the synthesis of acids or acid derivatives comprising ahydrofluoromethylenesulfonyl or -sulfinyl radical which makes itpossible to avoid the use of solvents which are expensive, unstable ordifficult to employ.

Another aim of the present invention is to provide a reaction of theabove type which makes it possible to obtain good yields and inparticular high conversion yields (CY, that is to say the yield ofdesired product obtained with respect to the amount of starting materialconsumed), that is to say of greater than 60%, preferably greater than70%.

Another aim of the present invention is to provide a process which ismultipurpose in nature, so that it can result equally well in theformation of acid salts, of acids or of acid halides.

It is also desirable for it to be possible to obtain essentially theacid corresponding to the sulfonic radical.

Another aim of the present invention is to provide a process which makesit possible to obtain derivatives of sulfinic nature.

These aims, and others which will become apparent subsequently, areachieved by means of a process for the synthesis of derivativescomprising a hydrofluoromethanesulfonyl or -sulfinyl radical comprisingat least the following stages:

-   a) a stage of condensation in a solvent of a thiolate (that is to    say, a monoalkyl sulfide salt), the counterion (that is to say, the    cation providing the electrical neutrality of the molecule) of which    is advantageously nonbasic (that is to say, a cation which is    hydrolyzed, for concentrations of 10⁻²N, only at pH values of    greater than 10, advantageously than 12), with a compound exhibiting    a carbon of sp³ hybridization carrying a hydrogen, a fluorine, a    heavy halogen, chosen from chlorine, bromine and iodine, and an    electron-withdrawing group chosen from fluorine and those for which    the σ_(p) is at least equal to 0.2, advantageously to 0.4;-   b) a stage of oxidation, advantageously of halogenation, preferably    of chlorination or of bromination, in the presence of an aqueous    phase;    said solvent of stage a) being chosen from water-immiscible    solvents, from aqueous phases and from the two-phase combination of    a water-immiscible solvent and of an aqueous phase, said aqueous    phases comprising at most ⅓ by weight of water-miscible nonaqueous    solvent; the ratio of the amount in equivalents of the thiolate to    the amount in moles of water being at most equal to 50.

When use is made of an aqueous phase comprising a water-misciblenonaqueous solvent, it is preferable for this solvent not to bebase-sensitive, that is to say for it not to be destroyed by thepresence of base; in particular, soluble esters and amides are to beavoided as far as possible. The expression “water-miscible” should beunderstood as meaning a solvent miscible in all proportions with water.The water-immiscible solvents are advantageously chosen from those whichexhibit a solubility in water, by weight, of at most 10%, that is to sayfor the water to be able to dissolve at most 10%, under standardtemperature and pressure conditions, of the water-immiscible solvent.Use may be made, as water-immiscible solvent, of chlorinated aromaticderivatives, indeed even certain ethers.

It is also preferable for the solubility in water of said immisciblesolvent to be at most 5% by weight, preferably 2% by weight.

Particular mention may be made, among immiscible solvents, of aromaticderivatives, optionally substituted, and in particular haloaromaticderivatives, such as mono-, di- or trichlorobenzenes.

Anisole, like the other phenol ethers, may be advantageous. However, theactivation by the oxygen or by aromatic ring hydrogen of aliphaticnature can interfere in the second stage and, in that case, it would beadvisable to remove the solvent before the “halogenation” stage.

However, according to the present invention, it is preferable to use, assolvent, an aqueous phase comprising little or, preferably, no miscibleorganic solvent but which can comprise dissolved salts and in particularhydrosoluble bases.

An important point of the present invention is that, in order tomaximize the yield, it is highly preferable to use a small amount ofwater. Thus, it is preferable for the ratio of the amount, expressed inequivalents, of the thiolate to the amount, expressed in moles, of waterto be at most equal to 30, advantageously to 20.

The amount of thiolate is expressed in equivalents in order to take intoaccount the case where use would be made of compounds comprising twosulfide functional groups or two thiolate functional groups. It is evenpossible to envisage, although doubtless not very advantageouseconomically, to use compounds comprising multiple thiol functionalgroups. According to the present invention, it is preferable for theamount of water to be sufficiently high to form a significant phase.Thus, the ratio of the amount, in equivalents, of the alkyl sulfide tothe amount of water (in the basic phase or phases), expressed in moles,is at least equal to 0.5, advantageously to 1, preferably to 1.5.

According to the present invention, it is preferable for said aqueousphases to comprise at most a quarter by weight of nonaqueous solvent,preferably at most a tenth.

It is also preferable for the [H₂O]/([H₂O]+[water-miscible solvent])molar ratio to be at least equal to 0.9, advantageously to 0.95.Finally, it is preferable to limit the concentration of the base in theaqueous phase to 0.5 equivalent per kg of aqueous phase.

It should be pointed out that the cationic thiolate which constitutesone of the substrates of stage A can be prepared in situ by the actionof a sulfide R—SH on a stronger base than R—S⁻.

The limitation on the concentration of the base and in particular of OH⁻is targeted only at the excess of base and thus does not take intoaccount the amount of base consumed in preparing the thiolate.

The thiolate can be written under the general formula R—S-M, where Mcorresponds to a metal or to a cation which, in combination with the OH⁻anion, constitutes a strong base, that is to say a base having anassociated acid exhibiting a pKa at least equal to 10, advantageously to12, preferably to 14.

The present invention can, in some cases, in particular when there is anorganic phase comprising a water-immiscible organic solvent, a phasetransfer agent. These agents are well known to a person skilled in theart and can in particular be chosen from oniums and from iniums, fromcrown ethers or from cryptand ethers, such as TDA1(N[CH₂—CH₂—O—CH₂—CH₂]₃N). According to the present invention, it ispreferable to operate with a small amount (or excess with respect to theamount necessary to neutralize the thiol to thiolate) of base in theaqueous phase, this amount advantageously being at least equal to 5%,advantageously to 10%, of the amount of said thiolate (R—S-M).

However, it is preferable for the aqueous medium of stage a) to comprisean amount of base at most equal to one times the amount of saidthiolate, preferably at most 50%, more preferably at most 30%.

According to the present invention, it has been shown that it isdesirable to use sulfides carried by an alkyl which is tertiary or ofbenzylic or allylic nature.

This activation of the carbon carrying the sulfur makes it possible tofacilitate the carbon-sulfur cleavage which is carried out in stage b).However, as the allylic radical is liable to result in troublesome sidereactions and polymerizations, it is preferable for the alkylderivatives to be restricted to those of tertiary or benzylic nature.

It is also possible to express the limitation on water-miscible polarorganic solvent by indicating that the molar ratio of the amount of apossible miscible polar solvent, expressed in moles, to the sum,expressed in equivalents, of the cocations of the sulfide and of thepossible base is advantageously at most equal to 1, preferably at mostequal to 1.5, more preferably at most equal to 1/10.

Mention may be made, among the advantageous compounds to be synthesized,of the hydrofluoromethylene radical compounds of formulae I and IV′

In this formula EWG is an electron-withdrawing group chosen fromfluorine and those for which the σ_(p) (Hammett constant) value is atleast equal to 0.2, advantageously to 0.4, and

represents either a halogen, advantageously chosen from chlorine andbromine, or an oxygen, itself carrying either a hydrogen or a negativecharge.

The reaction of the stage can be written as follows

In the above formulae, R represents an alkyl, that is to say an alcoholfrom which the OH functional group has been removed.

The halogenation reaction, which constitutes a preferred embodiment ofstage b), can be symbolized by one or more of the reactions below:

In this reaction, it is found that the halogen, symbolized here by

₂, oxidizes the sulfur, releases the alkyl radical in the form of analkyl halide, R-

and releases three acids H-

. This reaction results in a sulfinic derivative. This sulfinicderivative appeared in this equation in sulfinic acid itself. On theother hand, it is possible to recover the intermediate derivative ofIV′, which may constitute a reactant of value, and, on the other hand,the reaction is not halted at this stage, unless the amount of halogenis limited, as the sulfinic acid is oxidized to sulfonic derivatives;this derivative can be either a sulfonyl halide, according to thefollowing reaction:

whereas, depending on the operating conditions, the reaction can resultin the sulfonic acid or its salts, according to the reaction below:

According to the present invention it could be shown that the operatingconditions can be chosen in order to optimize the reaction eithertowards a sulfonyl halide or towards the sulfonic acid or its salts.

Thus, when it is desired to obtain an acid halide, it is desirable forstage b) to be carried out in the presence of a dissociated saltdissolved in aqueous phase, advantageously in an amount sufficient toreach and/or exceed a concentration of 1 N, preferably 2 N (as anion);the anion is advantageously a halide, preferably the halidecorresponding to the acid halide desired. This is particularly true whenthe acid halide desired is the acid chloride and the sulfonyl chloride.When use is made of a halide from an atomic row higher than that of thehalogen used, of course, the sulfonyl halide formed is thatcorresponding to the halide from the highest row in the medium.

Another characteristic which promotes the formation of the acid halideis the maintenance at a pH lying within a range from 4 to 9,advantageously from 5 to 8. As these two operating conditions are not inconflict, it is possible to combine them and thus to obtain a goodresult by using a saline solution at a pH ranging from 4 to 9.

It is preferable for the saline solution specified above to be asolution of an alkali metal halide (bromide and preferably chloride butnot iodide) at a concentration of halide of at least 1 N, preferably ofat least 2 N.

If it is desired to favor the formation of sulfonic acid, it ispreferable then to be positioned at acid pH values, that is to say pHvalues at most equal to 2, preferably at most equal to 1, preferably inthe vicinity of 0, and to avoid carrying out the chlorination orhydrolysis in a saline medium. It is thus advisable to avoid a saltcontent in the medium of greater than 1 N. It is also desirable, inorder to lower the salt content, to separate the aqueous phase from thesulfide phase which is generally formed during stage a). When thissulfide phase has not been formed, it is then desirable to carry out aliquid/liquid or liquid/solid extraction in order to recover thesulfide, to drive off the solvent and subsequently to treat the sulfidephase in an aqueous phase, so as to bring about cleavage between thesulfur atom and the carbon atom of the alkyl bonded to the sulfur.

One of the advantages of the present invention is to be able to carryout the synthesis of a halide (bromide and advantageously chloride) in asingle stage without changing the medium by carrying out the reaction ina concentrated aqueous medium in stage a) and by again using the aqueousmedium, after optionally removing the miscible or immiscible solvents,and cleaving with formation of a sulfinyl or sulfonyl group, asdescribed in stage b).

The reaction temperature is advantageously between 50° C. and 110° C.,preferably between 60° C. and 90° C.

The pressure is relatively high due to the fact that the compoundsexhibiting a carbon of sp³ hybridization carrying a hydrogen, a fluorineand a heavy halogen are often volatile, as is the case when EWG isfluorine, and that the said compound and the compound used as coolantunder the name of R-22 (that is to say, chlorodifluoromethane) are veryvolatile, which results in a high pressure in order to maintain theminimum of these compounds in a liquid phase and in particular anaqueous phase.

According to an advantageous form of the invention, theelectron-withdrawing group, such as that which is represented by EWG inthe preceding equations, is a highly fluorinated group; advantageously,the total carbon number of EWG (electron-withdrawing group), morespecifically Rf, is between 1 and 15, preferably between 1 and 10.

Thus, the electron-withdrawing group is advantageously chosen fromfluorine and the Rf groups; the term “Rf” is understood to mean aradical of formula:EWG′-(CX₂)_(p)—

-   -   where the X groups, which are alike or different, represent a        chlorine, a fluorine or a radical of formula C_(n)F_(2n+1), with        n being an integer at most equal to 5, preferably to 2, with the        condition that at least one of the X groups is fluorine,        fluorine advantageously carried by the carbon connected to the        sulfur;    -   where p represents an integer at most equal to 2;    -   where EWG′ represents an electron-withdrawing group (that is to        say, σ_(p) greater than zero, advantageously than 0.1,        preferably than 0.2), the possible functional groups of which        are inert under the conditions of the reaction, advantageously        fluorine or a perfluorinated residue of formula C_(n)F_(2n+1)        with n being an integer at most equal to 8, advantageously to 5.

As has already been mentioned, one of the preferred uses of theinvention is that which corresponds to the case where theelectron-withdrawing group is fluorine, which implies that the compoundis R-22, that is to say chlorodifluoromethane.

In the first stage, stage a), it is desirable for there to be a minimumamount of water and this minimum may be defined as follows. The ratio ofthe water, expressed in moles, to the cation present, more precisely thesum of the cations present, expressed in equivalents, is at least equalto 4, advantageously to 6, preferably to 8, in order to prevent themedium from being excessively polar and disturbing the solubility of thesubstrate comprising a carbon of sp³ hybridization carrying a hydrogen,a fluorine and a heavy halogen.

Advantageously, the cation or cations present in aqueous phase aremonovalent cations. It is preferable for these cations to be chosen fromquaternary phosphoniums, quaternary ammoniums and alkali metal cationsand advantageously the latter and, more preferably among the latter, thecations corresponding to sodium and corresponding to potassium.

In order to obtain satisfactory kinetics, it is preferable for thetemperature to be at least equal to 80° C. in stage a).

During the reaction, the halide formed R-

is recovered and then subjected to an alkali metal sulfide in order toreform the starting material, namely the mixed sulfide of alkyl and ofcation.

The following nonlimiting examples illustrate the invention.

EXAMPLE 1 Synthesis of Benzyl Difluoromethyl Sulfide

One equivalent of 40% by weight of sodium hydroxide in water was mixedwith one equivalent of benzyl mercaptan with R-22 (1.1 molarequivalents) at 60° C. for 1 h. The tests are carried out in a 500 mlHastelloy reactor at an autogenous pressure at 60° C. The pressure is3.5 bar. A chemical yield of 75%, by quantitative determination by ¹⁹FNMR, is obtained over two tests carried out under the same conditions.

EXAMPLE 2 Variation in the Various Parameters of the Synthesis of BenzylDifluoromethyl Sulfide from Benzyl Mercaptan

The procedure described above was repeated, with the duration beingmodified and with a large excess of R-22 (chlorodifluoromethane) beingintroduced gradually. The reaction was carried out at atmosphericpressure over a period of 4 h.

The details of the operating conditions are shown in the table below,along with the various yields. It should be remembered that DC meansdegree of conversion. This is the ratio of the amount of substrate underconsideration which has disappeared during the reaction to the startingamount. In this instance, the yield is calculated with respect to thebenzyl mercaptan initially charged. The RY is the reaction yield, thatis to say the amount of desired product with respect to the startingsubstrate under consideration and CY is the conversion yield, that is tosay the amount of desired product obtained divided by the amount ofsubstrate under consideration which has disappeared.

The various tests carried out are summarized in the following table:Conc. Sodium benzyl Benzyl hydroxide PTC mercaptan, R-22 Temp. DC (%) RY(%) CY (%) mercaptan mol.eq. Solvent 5 mol % % w/w mol.eq. (° C.) BTBDFS BDFS 100 mmol 2.5 TCB (1,2,4- TDA-1 11 2 90 100 82 82 groundtrichlorobenzene) ″ 2.5 ″ ″ 26 2 85 99.6 70 70 ground ″ ″ 2.5 ″ ″ 26 285 77 71 93 30% sol. ″ ″ 1.1 ″ ″ 26 2 85 74 66 89 30% sol. ″ ″ 1.1 ″ ″26 2 50 52 48 92 30% sol. ″ ″ 1.1 ″ No PTC 26 2 90 67 59 87 30% sol. ″ ″1.1 H₂O No PTC 33 3-4 95 80.7 74.3 92 30% sol. ″ 1.1 H₂O TDA-1 33 4 9580.7 74.6 92 30% sol. ″ 1.1 KOH H₂O No PTC 50 3 95 83 75 90 50% ″ 2 NaOHH₂O ″ 31 3 95 82 75 92 30% sol. 1.5 mol   1.1 NaOH H₂O ″ 33.4 1 P = 8.5bar 95 79 75.3 95 30% In the table, BT means benzylthiol, that is to saybenzyl mercaptan. BDFS means benzyl difluoromethyl sulfide.

EXAMPLE 3 Comparative Example Role of the Water

The conditions of test 2k were repeated, the amount of water beingsignificantly increased so that there are 5 mol of benzyl mercaptan perkg of water present in the phase. The result obtained shows a dramaticdecline in the yield, namely yields of the order of 15%.

EXAMPLE 4 Chlorination Test

75 g of water are charged in a reactor and then 26.1 g ofdifluoromethylthiobenzyl are added.

The reaction medium is two-phase and colorless. The mixture is cooled to10° C. and chlorine (32 g) is slowly introduced into the material.

In order to maintain the temperature at 10° C. despite the very highexothermicity, the jacket set temperature is regulated at −5° C.

The introduction of chlorine is halted when the exothermicity ceases andwhen the reaction medium begins to turn yellow.

The chlorine is introduced over 3 hours (31.6 exactly).

At the end of the 3 hours, the reaction medium is allowed to return toambient temperature, flushing is carried out with nitrogen and stirringis halted. The two phases readily separate on settling. The aqueousphase is clear and colorless. The organic phase is clear and yellow.

The organic phase is dried over MgSO₄ and filtered through a sinteredglass funnel.

37.6 g of liquid phase are recovered, the analysis of which by gaschromatography indicates a chemical yield of difluoromethanesulfonylchloride of 82%.

After distillation, 14.3 g of difluoromethanesulfonyl chloride with apurity of greater than 99% are obtained (boiling point: 66° C. under 300mbar).

1. A process for the synthesis of compounds having ahydrofluoromethylenesulfonyl radical from an alkyl thiolate, the processcomprising the steps of: a) reacting (1) an alkyl thiolate and anassociated cation with (2) a compound exhibiting a carbon of sp³hybridization carrying a hydrogen, a fluorine, a heavy halogen selectedfrom the group consisting of chlorine, bromine and iodine, and anelectron-withdrawing group which is fluorine or a group having a Hammettconstant (σ_(p) ) value of at least equal to 0.2, in a solvent; and b)oxidizing the compound formed in step a) in the presence of an aqueousphase; said solvent of step a) being a water-immiscible solvent, anaqueous phase or a two-phase combination of a water-immiscible solventand of an aqueous phase, said aqueous phase comprising at most ⅓ byweight of water-miscible nonaqueous solvent; with a ratio of the amount,in equivalents, of the alkyl sulfide to the amount, in moles, of waterbeing at most equal to
 50. 2. The process as claimed in claim 1, whereinthe solvent of step a) further comprises a strong base with a pKa of theassociated acid at least equal to 10, in an amount, expressed inequivalents, of at least equal to 5% of the amount of said thiolate. 3.The process as claimed in claim 2, wherein said amount of strong base isat most equal to the amount of said thiolate.
 4. The process as claimedin claim 2, wherein, in step a), the solvent further contains a polarsolvent with a molar ratio of the amount of said polar solvent,expressed in moles, to the sum, expressed in equivalents, of theco-cations of the sulfide and of the base is at most equal to
 1. 5. Theprocess as claimed in claim 1, wherein the electron-withdrawing group isfluorine or a (Rf) groups of formula:EWG′-(CX₂)_(p)— Wherein: the X groups, which are identical or different,represent a chlorine, a fluorine or a radical of formula C_(n)F_(2n+1),with n being an integer at most equal to 5, with the proviso that atleast one of the X groups is fluorine; p represents an integer at mostequal to 2; and EWG′ represents an electron-withdrawing group.
 6. Theprocess as claimed in claim 5, wherein the total number of carbon atomsin the group Rf is between 1 and
 15. 7. The process as claimed in claim1, wherein the electron-withdrawing group is fluorine.
 8. The process asclaimed in claim 1, wherein the ratio of the water, expressed in moles,to the cation, expressed in equivalents, is at least equal to
 4. 9. Theprocess as claimed in claim 1, wherein said cation is monovalent. 10.The process as claimed in claim 9, wherein said cation is phosphonium, aquaternary ammoniums or an alkali metal.
 11. The process as claimed inclaim 1, wherein stage b) is carried out either in the presence of adissociated salt dissolved in the reaction mixture or by maintaining apH within the range from 4 to 9, in order to obtain an acid halide. 12.The process as claimed in claim 1, wherein the process is carried out ata temperature at least equal to 80° C.